An expanded metabolic pathway for androgen production by commensal bacteria PMID: 40259019

ADC Targets in Oncology

2026-04-10

An expanded metabolic pathway for androgen production by commensal bacteria

Nat Microbiol. 2025 May;10(5):1084-1098. doi: 10.1038/s41564-025-01979-9.

Taojun Wang ^# ¹ ² , Saeed Ahmad ^# ³ ⁴ , Angélica Cruz-Lebrón ⁵ , Sarah E Ernst ⁵ , Kelly Yovani Olivos Caicedo ⁶ , Yoon Jeong ³ ⁴ , Briawna Binion ¹ ² , Pauline Mbuvi ⁴ ⁷ , Debapriya Dutta ⁴ ⁷ , Francelys V Fernandez-Materan ¹ ² , Adam M Breister ⁸ , Elizabeth Tang ⁹ , Jae Won Lee ¹⁰ , Jason D Kang ¹¹ , Spencer C Harris ¹¹ , Shigeo Ikegawa ¹² , H Rex Gaskins ¹ ¹³ ¹⁴ , John W Erdman Jr ¹³ ¹⁴ , Glen Yang ⁷ , Isaac Cann ¹ ² ¹³ , Steven L Daniel ¹ , Phillip B Hylemon ¹¹ ¹⁵ , Karthik Anantharaman ⁸ , Rafael C Bernardi ¹⁶ , João M P Alves ⁶ , Karen S Sfanos ¹⁷ , Joseph Irudayaraj ¹⁸ ¹⁹ ²⁰ ²¹ ²² ²³ , Jason M Ridlon ²⁴ ²⁵ ²⁶ ²⁷ ²⁸ ²⁹

Affiliations

1. Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, IL, USA.
2. Carl R. Woese Institute for Genomic Biology, Urbana, IL, USA.
3. Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL, USA.
4. Biomedical Research Center, Mills Breast Cancer Institute, Carle Foundation Hospital, Urbana, IL, USA.
5. Departments of Pathology, Oncology, and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
6. Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
7. Department of Urology, Carle Foundation Hospital, Urbana, IL, USA.
8. Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA.
9. Department of Physics, University of Illinois Urbana-Champaign, Urbana, IL, USA.
10. Department of Biotechnology, Sungshin Women's University, Seoul, South Korea.
11. Stravitz-Sanyal Institute for Liver Disease & Metabolic Health, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
12. Genmaikoso Co. Ltd, Hokkaido, Japan.
13. Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
14. Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
15. Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
16. Department of Physics, Auburn University, Auburn, AL, USA.
17. Departments of Pathology, Oncology, and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
18. Carl R. Woese Institute for Genomic Biology, Urbana, IL, USA. [email protected].
19. Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL, USA. [email protected].
20. Biomedical Research Center, Mills Breast Cancer Institute, Carle Foundation Hospital, Urbana, IL, USA. [email protected].
21. Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA. [email protected].
22. Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, USA. [email protected].
23. Carle-Illinois College of Medicine, University of Illinois Urbana-Champaign, Urbana, IL, USA. [email protected].
24. Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, IL, USA. [email protected].
25. Carl R. Woese Institute for Genomic Biology, Urbana, IL, USA. [email protected].
26. Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA. [email protected].
27. Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, USA. [email protected].
28. Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA. [email protected].
29. Center for Advanced Study, University of Illinois Urbana-Champaign, Urbana, IL, USA. [email protected].
# Contributed equally.

Abstract

Commensal bacteria have been implicated in the modulation of steroid Hormones, including circulating androgen levels in the host. However, the microbial genetic pathways involved in androgen production have not been fully characterized. Here we identify a microbial gene encoding an enzyme that catalyses the conversion of androstenedione to epitestosterone in the gut microbiome member Clostridium scindens and named this gene desF. We demonstrate that epitestosterone impacts androgen receptor-dependent prostate Cancer cell proliferation in vitro. We also demonstrate that stool desF levels are elevated in patients with prostate Cancer who are unresponsive to abiraterone/prednisone therapy. Bacterial isolates from urine or prostatectomy tissue produced androgens, and 17β-hydroxysteroid dehydrogenase activity encoded by the desG gene was detected in strains of the urinary tract bacterium Propionimicrobium lymphophilum. Furthermore, we demonstrate that urinary androgen-producing Bacterial strains can promote prostate Cancer cell growth through metabolism of cortisol and prednisone. Abiraterone, which targets host desmolase (CYP17A1), a rate-limiting enzyme in adrenal steroidogenesis, does not inhibit Bacterial desmolase (DesAB), whereas the conversion of prednisone to androgens by DesAB, DesF and DesG drives androgen-receptor-dependent prostate Cancer cell line proliferation in vitro. Our results are a significant advance in steroid microbiology and highlight a potentially important role for gut and urinary tract bacteria in host endocrine function and drug metabolism.